Classical pathway of the complement system


The complement system is a part of the immune system that consists of a cascade of interactions between various plasma proteins called complements. These proteins are normally inactive in the blood, but they become activated when they encounter certain triggers, such as pathogens or immune complexes. The activation of the complement system leads to various outcomes, such as opsonization, inflammation, and cell lysis, that help to eliminate the invaders and restore homeostasis.

There are three main pathways that activate the complement system: the classical pathway, the lectin pathway, and the alternative pathway. These pathways differ in their initiation mechanisms, but they converge at a common point where they cleave the C3 protein, which is the central component of the complement system. The cleavage of C3 produces two fragments: C3a and C3b. C3a is an anaphylatoxin that mediates inflammation, while C3b is an opsonin that enhances phagocytosis. C3b also forms complexes with other complement proteins to generate C5 convertase, which cleaves C5 into C5a and C5b. C5a is another anaphylatoxin that amplifies inflammation, while C5b initiates the formation of the membrane attack complex (MAC), which is a pore-like structure that inserts into the cell membrane and causes cell lysis.

The classical pathway of the complement system is the oldest and most well-studied pathway. It is mainly activated by the formation of antigen-antibody complexes (immune complexes), which are molecular structures that result from the binding of antigens (foreign substances) to antibodies (specific proteins produced by B cells). The antibodies involved in this pathway are usually IgG or IgM, which are two types of immunoglobulins that have different structures and functions. IgG is the most abundant antibody in the blood and can bind to four antigens at a time, while IgM is the first antibody produced during an immune response and can bind to ten antigens at a time.

The classical pathway can also be activated by other molecules that can bind to the C1 protein, which is the first component of this pathway. These molecules include apoptotic cells (cells that undergo programmed cell death), necrotic cells (cells that die due to injury or disease), C-reactive protein (CRP) (an acute phase protein that increases during inflammation), bacterial polysaccharides (sugars on the surface of bacteria), and nucleic acids (DNA or RNA). These molecules can trigger the classical pathway in an antibody-independent manner, meaning that they do not require antibodies to activate the complement system.

The classical pathway involves a series of sequential reactions that involve nine complement proteins: C1 to C9. Each of these proteins has subunits that are designated by letters: a or b for larger subunits and b or a for smaller subunits. The exception is C2, which has a larger subunit called a and a smaller subunit called b. The classical pathway can be divided into four stages: initiation, formation of C3 convertase, formation of C5 convertase, and formation of MAC. Each stage will be explained in detail in the following sections.